Cardiovascular aging as a modifiable biological process: Mechanisms, clinical phenotypes, and translational opportunities

Abstract

Cardiovascular aging, a primary driver of the increasing prevalence of cardiovascular disease in older adults, involves a complex biological basis beyond mere chronological age. From a geroscience perspective, aging is now understood as a dynamic and potentially modifiable process, believed to be governed by interconnected molecular hallmarks such as cellular senescence, mitochondrial dysfunction, epigenetic remodeling, telomere attrition, and impaired proteostasis. This review synthesizes recent advancements in aging biology, illustrating how these core hallmarks appear to converge on major cardiovascular phenotypes including atherosclerosis, heart failure with preserved ejection fraction, hypertension, and arrhythmia through shared mechanisms. These mechanisms encompass endothelial dysfunction, vascular smooth muscle cell phenotypic switching, myocardial fibrosis, chronic inflammation, and electrophysiological instability. We also summarize current approaches to assessing cardiovascular aging, which include imaging-based indices, circulating biomarkers, and emerging epigenetic clocks capable of quantifying biological age and age acceleration. At the interventional level, growing preclinical and early-phase clinical evidence suggests that geroprotective strategies show promise for altering cardiovascular aging trajectories. These strategies include lifestyle modification, metabolic regulation, senotherapeutics, and modulation of mechanistic target of rapamycin and nicotinamide adenine dinucleotide pathways. Nevertheless, significant challenges persist, such as the absence of standardized aging assessment frameworks, uncertainties regarding long-term safety, and the necessity for rigorously designed clinical trials with aging-related endpoints. By connecting the molecular hallmarks of aging with clinically measurable cardiovascular phenotypes and novel therapeutic strategies, this review underscores cardiovascular aging as a clinically tractable and translationally relevant model for transforming geroscience principles into actionable approaches for disease prevention and healthy longevity.

Key Words: Cardiovascular aging; Geroscience; Hallmarks of aging; Translational medicine; Biomarkers; Intervention

Core Tip: This review synthesizes current evidence that cardiovascular aging is driven by interconnected hallmarks: Cellular senescence, mitochondrial dysfunction, epigenetic remodeling, telomere attrition, and impaired proteostasis which converge on atherosclerosis, heart failure with preserved ejection fraction, hypertension, and arrhythmia. We highlight emerging assessment tools including imaging-based indices, circulating biomarkers, and epigenetic clocks for quantifying biological age, and critically evaluate geroprotective strategies ranging from lifestyle modification to senotherapeutics and nicotinamide adenine dinucleotide/mechanistic target of rapamycin modulation. Bridging geroscience principles with cardiovascular medicine, this review positions cardiovascular aging as a clinically modifiable target for promoting healthy longevity.

INTRODUCTION

The aging of the global population represents one of the 21^st century’s most profound demographic shifts, making cardiovascular diseases the leading cause of morbidity and mortality among older adults[1]. Epidemiological research consistently reveals an exponential increase in cardiovascular risk with advancing age, thus establishing aging as the predominant risk factor across various cardiovascular phenotypes[2]. Aging is not solely a chronological progression; it manifests clinically as frailty, multimorbidity, and other geriatric syndromes that collectively diminish health span, the duration of life spent in good health, free from chronic diseases and disability. Cardiovascular aging significantly contributes to these conditions, and comprehending its biological foundations is crucial for extending health span, rather than merely lifespan.

Traditionally, aging has been viewed as an inevitable and irreversible factor in the development of cardiovascular disease. However, significant advancements in basic and translational research over the past decade have fundamentally altered this perspective. Aging is now understood as a biologically regulated process, driven by a series of interconnected molecular and cellular mechanisms that are, in principle, modifiable[3,4]. This paradigm shift has led to the emergence of geroscience, a field dedicated to understanding how targeting fundamental aging processes might simultaneously delay the onset or progression of multiple age-related diseases. In 2023, López-Otín et al[3] expanded the conceptual framework of “hallmarks of aging” to include twelve interrelated features, such as cell senescence, mitochondrial dysfunction, epigenetic alterations, telomere attrition, and impaired proteostasis. This framework offers a unifying perspective through which cardiovascular aging can be comprehended not as a collection of isolated insults, but as the consequence of an integrated network of aging mechanisms that progressively diminish cardiovascular resilience. Among these hallmarks, we prioritize those most directly implicated in cardiovascular pathology and those amenable to current assessment and intervention strategies. Cell senescence and the senescence-associated secretory phenotype (SASP) have been identified as crucial contributors to chronic inflammation and tissue remodeling, while epigenetic alterations provide a basis for quantifying biological aging through DNA methylation-based clocks.

Crucially, increasing evidence suggests that biological age, rather than chronological age alone, more accurately predicts cardiovascular structure, function, and clinical outcomes[5]. Epigenetic age acceleration has been associated with subclinical atherosclerosis, heart failure, and cardiovascular mortality, thereby emphasizing the clinical relevance of aging biology in stratifying cardiovascular risk[6,7].

Against this backdrop, the present review aims to synthesize the current understanding of the molecular hallmarks of aging and delineate their convergence on key cardiovascular phenotypes. We further discuss emerging tools for assessing cardiovascular aging and evaluate the translational potential of interventions targeting aging. By framing cardiovascular aging as a quantifiable and modifiable process, this review highlights its value as a model system for bridging geroscience and cardiovascular medicine (Figure 1). Unlike recent reviews that primarily focus on individual molecular hallmarks or specific therapeutic classes, the present review offers an integrated, clinically anchored framework that connects aging mechanisms to distinct cardiovascular phenotypes, synthesizes available assessment tools, and critically evaluates translational strategies across the full spectrum of interventions. This integrated approach encompassing molecular mechanisms, clinical phenotyping, multimodal assessment, and translational interventions distinguishes our review from existing contributions that typically address only one or two of these dimensions.

Figure 1 Cardiovascular aging arises from interconnected molecular defects, including DNA damage, mitochondrial dysfunction, and nutrient-sensing imbalance leading to cellular senescence and chronic inflammation (senescence-associated secretory phenotype, inflammaging). These processes converge to cause vascular stiffness, fibrosis, and arrhythmia, ultimately manifesting as cardiovascular diseases. γ-H2AX: The phosphorylated form of histone H2AX; 8-oxo-dG: 8-hydroxy-2’-deoxyguanosine; mtROS: Mitochondrial reactive oxygen species; SIRT: Sirtuin (silent information regulator); PGC-1α: Peroxisome proliferator-activated receptor gamma coactivator 1-alpha; mTOR: Mechanistic target of rapamycin; AMPK: Adenosine 5’-monophosphate-activated protein kinase; SASP: Senescence-associated secretory phenotype; IL: Interleukin; TNF-α: Tumor necrosis factor α; MMP-9: Matrix metalloproteinase-9; ECs: Endothelial cells; VSMCs: Vascular smooth muscle cells; EF: Ejection fraction.

Given the broad and integrative scope of this review, we employed a narrative review approach. We identified literature through targeted searches in PubMed and Web of Science up to the end of 2025, utilizing combinations of keywords such as “cardiovascular aging”, “hallmarks of aging”, “cellular senescence”, “epigenetic clocks”, “senotherapeutics”, and “NAD⁺ metabolism”. Additional references were retrieved from the bibliographies of key articles and recent reviews. The selection of studies was guided by their relevance to the major themes of this review: Molecular mechanisms, clinical phenotypes, assessment tools, and therapeutic interventions.

THE MOLECULAR AND CYTOLOGICAL BASIS OF AGING

Aging represents the primary risk factor for the onset and progression of cardiovascular diseases. At a fundamental molecular and cellular level, aging is defined by a set of conserved biological processes collectively known as the hallmarks of aging that dictate an organism’s lifespan and functional reserve. These classical hallmarks include genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, dysregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication[8]. These processes do not operate in isolation but rather form an interconnected network that progressively impairs cardiovascular structure and function.

Within the cardiovascular system, age-related molecular defects converge on critical cellular populations, such as endothelial cells, vascular smooth muscle cells (VSMCs), cardiomyocytes, and fibroblasts. This convergence ultimately influences vascular stiffness, myocardial remodeling, and electrophysiological vulnerability. The following sections will highlight several hallmarks of aging particularly relevant to cardiovascular aging and explore their mechanistic connections to cardiovascular pathology (Table 1).

Table 1 Major molecular mechanisms of cardiovascular aging discussed in this review[111-117].

Aging mechanism or biomarker category	Representative biomarkers or pathways	Sample and assessment method	Potential clinical or cardiovascular relevance	Ref.
DNA damage and telomere attrition	γ-H2AX, 8-oxo-dG, telomere length	Immunofluorescence, comet assay, qPCR in leukocytes	DNA damage and telomere shortening induce EC and VSMC senescence, accelerating atherosclerosis and myocardial aging	Blackburn et al[32]; Deng et al[33]; Li et al[34]; Bloom et al[41]
Mitochondrial dysfunction and oxidative stress	mtROS, SIRT3/PGC-1α, ATP loss	Seahorse assay, ROS probes, WB	Excess mtROS triggers vascular inflammation and cardiac fibrosis; restoring SIRT3 improves endothelial function	Dai et al[22]; Goodman et al[23]; Dai et al[24]; Bachschmid et al[40]; Bloom et al[41]; Mondragon et al[49]
Nutrient sensing imbalance (mTOR/AMPK/SIRT axis)	mTOR, AMPK, SIRT1	WB, phosphoprotein analysis	Overactive mTOR and low SIRT1/AMPK promote metabolic inflammation, endothelial dysfunction, and cardiac hypertrophy	Zhan et al[46]; Fontana et al[88]; Qu et al[89]; Justice et al[96]; Greenberg et al[97]; Zhang et al[99]
Cellular senescence and SASP secretion	p16INK4a, p21CIP1, SA-β-gal, IL-6/IL-1β/TNF-α (SASP)	qPCR, IHC, ELISA	Senescent ECs and VSMCs release SASP, chronic inflammation, plaque instability and impaired repair	Di Micco et al[9]; Gorgoulis et al[12]; Owens et al[15]; Mehdizadeh et al[16]; Wang et al[18]; Honda et al[19]; Garrido et al[94]; Karnewar et al[95]
Clonal hematopoiesis of indeterminate potential	DNMT3A, TET2, ASXL1, JAK2 mutations; VAF ≥ 2%	Targeted DNA sequencing (NGS) in peripheral blood	Identifies an age-related hematopoietic state associated with atherosclerotic CVD, heart failure, arrhythmias, and valvular disease	Jaiswal et al[111]; Tan et al[112]
Stem cell exhaustion and impaired regeneration	CD34+ EPCs, c-Kit+ cardiac progenitors	Flow cytometry, colony forming assay	Reduced progenitor pool limits endothelial repair and neovascularization in aging hearts and vessels	Mehdizadeh et al[16]; Sorokina et al[75]
Inflammaging and immune dysregulation	CRP, IL-6, NLRP3 inflammasome activation	ELISA, transcriptomics	Low-grade systemic inflammation drives endothelial activation and cardiac fibrosis; IL-1β blockade reduces events in elderly	Khalafi et al[56]; Müller and Di Benedetto[57]; Danesh et al[58]; Zhou et al[59]; Thompson and Nidorf[92]; Tardif et al[93]
Altered intercellular communication (exosomes/SASP spread)	Exosomal miR-21/miR-126, NF-κB, NLRP3	Nanoparticle tracking, qPCR, WB	Senescent cell-derived exosomes propagate inflammatory signals and fibrotic remodeling across cardiac tissues	Acosta et al[10]; Admasu et al[11]; Gorgoulis et al[12]
Extracellular vesicles	EV surface antigens (EV aging index); endothelial micro-vesicles (EMVs: CD31+/42b-)	Nanoparticle tracking, flow cytometry, ELISA in serum/plasma	EVs mediate endothelial dysfunction and senescence-associated vascular dysfunction; EMVs increase with age and correlate with endothelial vasodilator dysfunction; EV aging index stratifies CV risk	Burrello et al[80]; DeSouza et al[113]
Epigenetic aging biomarkers	Horvath clock, Hannum clock, PhenoAge, GrimAge, epigenetic age acceleration	DNA methylation arrays or sequencing in peripheral blood	Quantify biological age and age acceleration; associated with subclinical atherosclerosis, arterial stiffness, heart failure, and cardiovascular mortality	Allegra et al[27]; Sánchez-Cabo et al[28]; Chen et al[29]; Fox et al[30]; Joyce et al[31]; Yamada[81]; Hannum et al[82]; Horvath[83]; Ammous et al[84]; Feng et al[85]
Proteomic aging clocks	Multi-marker protein panels, including 204-protein and organ-specific proteomic age scores	Olink, SomaScan, or mass-spectrometry-based plasma proteomics	Estimate systemic and organ-specific biological age and predict incident cardiovascular disease, multimorbidity, and mortality	Argentieri et al[114]; Robinson et al[115]
Metabolomic and lipidomic aging scores	MetaboPhenoAge; lipidomic metabolic age score	Mass spectrometry or NMR spectroscopy in plasma or serum	Capture metabolic aging and may predict incident cardiovascular disease and cardiometabolic risk beyond chronological age	You et al[116]; Wang et al[117]
Circulating inflammatory and myocardial stress biomarkers	hsCRP, IL-6, TNF-α, GDF-15, sST2, galectin-3, NT-proBNP, hs-cTn	ELISA, immunoassay, serum or plasma	Reflect inflammaging, myocardial stress, fibrosis, and subclinical cardiovascular injury; may support risk stratification in older adults	Giovannini et al[73]; Oppong et al[76]; Parikh et al[77]; Keng et al[78]
Circulating microRNAs	miR-23a-3p, miR-92a-3p, and other age-associated microRNAs	qPCR, small-RNA sequencing in plasma or serum	May reflect vascular inflammation, endothelial dysfunction, and cardiovascular risk in older adults	La Grotta et al[79]

The table integrates mechanistic biomarkers, circulating indicators, molecular aging clocks, and multi-omics measures relevant to cardiovascular aging. Evidence categories reflect the predominant supporting data and do not imply clinical validation or routine applicability. mTOR: Mechanistic target of rapamycin; AMPK: Adenosine 5’-monophosphate-activated protein kinase; SIRT: Sirtuin (silent information regulator); SASP: Senescence-associated secretory phenotype; γ-H2AX: The phosphorylated form of histone H2AX; 8-oxo-dG: 8-hydroxy-2’-deoxyguanosine; mtROS: Mitochondrial reactive oxygen species; SIRT: Sirtuin (silent information regulator); PGC-1α: Peroxisome proliferator-activated receptor gamma coactivator 1-alpha; IL: Interleukin; TNF-α: Tumor necrosis factor α; ATP: Adenosine triphosphate; VAF: Variant allele fraction; CD: Cluster of differentiation; CRP: C-reactive protein; NLRP3: NOD-like receptor thermal protein domain associated protein 3; NF-κB: Nuclear factor kappa-B; EV: Extracellular vesicle; EMV: Endothelial microvesicle; hsCRP: High-sensitivity C-reactive protein; GDF-15: Growth differentiation factor-15; sST2: Soluble suppression of tumorigenicity 2; NT-proBNP: N-terminal pro-B-type natriuretic peptide; hs-cTn: High-sensitivity cardiac troponin; WB: Western blot; qPCR: Quantitative polymerase chain reaction; ROS: Reactive oxygen species; IHC: Immunohistochemistry; ELISA: Enzyme-linked immunosorbent assay; NGS: Next-generation sequencing; NMR: Nuclear magnetic resonance; CVD: Cardiovascular disease; CV: Cardiovascular; EC: Endothelial cell; EPC: Endothelial progenitor cell; VSMC: Vascular smooth muscle cell.

Cellular senescence

Cellular senescence describes a state of irreversible cell cycle arrest where cells remain metabolically active after exposure to triggers like replicative exhaustion, DNA damage, oxidative stress, or other forms of cellular injury. Senescent cells are characterized by the upregulation of cyclin-dependent kinase inhibitors, including p16INK4a and p21CIP1, along with the acquisition of a SASP[9].

The SASP consists of a complex mixture of pro-inflammatory cytokines, chemokines, matrix-degrading enzymes, and pro-fibrotic factors that collectively remodel the local tissue microenvironment[10]. Beyond reinforcing senescence in an autocrine manner, SASP factors can induce secondary (paracrine) senescence in neighboring cells, thereby exacerbating tissue dysfunction[11]. While primary and secondary senescence appear to differ in their initial triggers and molecular signatures, the precise mechanistic basis of this distinction remains incompletely defined.

Primary senescence is primarily triggered by damage types such as carcinogenic signals, genotoxic damage, critically short telomeres, mitochondrial damage, viral or bacterial infections, oxidative damage, nutritional imbalance, and mechanical stress[12]. In contrast, secondary senescence is predominantly activated by extracellular mediators of inflammation and fibrosis, including CCL2, interleukin (IL)-1β, IL-6, IL-8, and transforming growth factor (TGF)-β[13]. Notably, although cellular senescence is vital for normal development, wound healing, and tumor suppression, senescent cells that are not efficiently cleared by the immune system[14] can accumulate and drive chronic pathologies like cardiovascular disease[15,16]. Therefore, the overall impact of senescence on cardiovascular health is highly context-dependent, influenced by the specific cell type, tissue microenvironment, and the efficiency of immune-mediated clearance. Indeed, numerous studies have shown that cellular senescence is associated with age-related vascular diseases, including atherosclerosis, ischemic cardiomyopathy, and heart failure with preserved ejection fraction (HFpEF)[17-19]. This evidence suggests that cellular senescence represents a significant pathological link in atherosclerosis, hypertension, and heart failure.

Mitochondrial dysfunction

Mitochondria are crucial for cellular function, not only generating adenosine triphosphate but also regulating redox homeostasis, calcium dynamics, metabolic signaling, and cell fate. Consequently, mitochondrial dysfunction is a hallmark of aging and a significant contributor to cardiovascular decline[20]. Mitochondria in senescent cells also influence the composition and intensity of the SASP[21].

As age progresses, cardiomyocytes and vascular cells exhibit reduced mitochondrial oxidative phosphorylation efficiency, increased electron transport chain leakage, and excessive production of reactive oxygen species (ROS)[22]. Concurrently, age-associated impairments in mitochondrial dynamics, such as an imbalanced fusion-fission process and defective mitophagy, lead to the accumulation of damaged and dysfunctional mitochondria[23].

In the heart, mitochondrial dysfunction diminishes energetic reserves, compromises calcium handling, and reduces tolerance to hemodynamic and metabolic stress, thereby accelerating the progression to heart failure. Within the vasculature, excessive mitochondrial ROS promotes endothelial dysfunction, inflammatory activation, and arterial stiffening, fostering an environment conducive to atherosclerosis and hypertension[24]. Notably, emerging evidence indicates that dysfunctional mitochondria actively modulate the intensity and composition of the SASP, thereby linking mitochondrial failure to chronic inflammation and cellular senescence in aging cardiovascular tissues.

Epigenetic alterations and biological clocks

Epigenetic alterations are a fundamental mechanism through which aging reshapes gene expression without altering the underlying DNA sequence. Age-associated epigenetic changes encompass shifts in DNA methylation patterns, aberrant histone post-translational modifications, altered chromatin accessibility, and dysregulation of non-coding RNAs[3]. These modifications collectively contribute to transcriptional drift and a progressive imbalance in pathways governing metabolism, inflammation, proteostasis, and stress responses.

These epigenetic alterations may contribute to transcriptional changes and imbalances in genes related to aging, which, in turn, trigger pathophysiological processes such as protein homeostasis disorders, mitochondrial dysfunction, and inflammatory responses[25,26]. The “epigenetic clocks” identified based on these molecular alterations can predict biological age[27]. However, the clinical application of these clocks is limited by several factors, including high costs, limited standardization across platforms, uncertain reproducibility, and insufficient interventional data demonstrating that modifying epigenetic age improves cardiovascular outcomes. Furthermore, most clocks have been developed and validated predominantly in populations of European ancestry, which raises important questions regarding their generalizability and applicability to other ethnic and ancestral groups. Implementation studies conducted in real-world clinical settings are currently limited. A number of large-scale population-based and multi-omics studies have shown that epigenetic age acceleration is associated with an increased risk of atherosclerosis, heart failure, and hypertension[7,28,29]. Furthermore, ideal cardiovascular health has been linked to slower epigenetic aging and a lower risk of cardiovascular events[30,31]. These findings indicate that epigenetics is not only a molecular marker of aging but may also become a new target for intervening in cardiovascular aging.

Telomere shortening and genomic instability

Telomere shortening stands as one of the earliest proposed molecular mechanisms underlying aging. Telomeres progressively shorten with each cell division, and once they reach a critically short length, they trigger a DNA damage response. This response leads to genomic instability and ultimately induces either cellular senescence or apoptosis[32]. Epidemiological and genetic investigations have established a link between shorter leukocyte telomere length and an elevated risk of atherosclerosis, myocardial infarction, and heart failure[33]. Experimental models, including those using induced pluripotent stem cell-derived cardiomyocytes, further demonstrate that telomere shortening activates aging-associated transcriptional programs and impairs myocardial contractile function[34]. These findings support the concept that telomere integrity acts as a determinant of cardiovascular susceptibility rather than merely a passive indicator of chronological age. However, it is important to acknowledge the limitations of leukocyte telomere length as a surrogate for tissue-specific cardiovascular aging, and the variability in measurements across studies complicates direct comparisons. Furthermore, the evidence connecting leukocyte telomere length to cardiovascular disease remains a subject of debate, with conflicting results observed across various studies. The observational nature of most available studies prevents definitive conclusions regarding causality, and it is plausible that cardiovascular disease itself may accelerate telomere attrition.

Loss of proteostasis

Proteostasis, which encompasses the meticulous regulation of protein synthesis, folding, trafficking, and degradation, is fundamental for maintaining cellular function and resilience to stress. This delicate balance is upheld by the synchronized actions of molecular chaperones, the ubiquitin-proteasome system, and the autophagy-lysosomal pathway. Aging disrupts each of these critical components, leading to the accumulation of misfolded and aggregated proteins and the activation of endoplasmic reticulum stress responses[35].

Within the heart, compromised proteostasis contributes to contractile dysfunction, cardiomyocyte apoptosis, and a diminished adaptive capacity under stress conditions[36]. In the vasculature, altered extracellular matrix turnover and excessive collagen cross-linking lead to increased arterial stiffness and reduced compliance[37]. Experimental studies showing that enhancing autophagy can delay cardiac aging and improve function further underscore proteostasis as a modifiable factor influencing cardiovascular aging[38].

THE ROLE OF AGING MECHANISMS IN THE CARDIOVASCULAR SYSTEM

The molecular and cellular changes associated with aging do not occur in isolation. Instead, these alterations converge on specific cardiovascular cell types and tissue architectures, progressively eroding cardiovascular resilience and functional reserve. Through their coordinated effects on endothelial cells, VSMCs, cardiomyocytes, fibroblasts, and immune cells, aging mechanisms translate molecular damage into organ-level dysfunction. In this section, we will delineate how the hallmarks of aging manifest across key cardiovascular compartments and give rise to characteristic pathophysiological phenotypes (Figure 2).

Figure 2 Mechanism diagram of aging and cardiovascular diseases. A: Aging and vascular dysfunction; B: Aging and atherosclerosis; C: Aging and myocardial fibrosis; D: Aging and hypertension. SASP: Senescence-associated secretory phenotype; NO: Nitric oxide; ROS: Reactive oxygen species; SMA: Smooth muscle actin; eNOS: Endothelial nitric oxide synthase; ET-1: Endothelin-1; IL: Interleukin; TNF-α: Tumor necrosis factor α; TGF-β: Transforming growth factor-β; Ang II: Angiotensin II.

Endothelial dysfunction and vascular stiffness

Vascular endothelial cells form a crucial barrier for maintaining vascular homeostasis, and their dysfunction represents an early hallmark of cardiovascular aging[39]. As individuals age, endothelial cells progressively exhibit diminished mitochondrial function[40], along with an accumulation of DNA damage and telomere shortening[41]. These cellular changes lead to reduced nitric oxide (NO) production and elevated oxidative stress levels[42]. These alterations are believed to impair the blood vessels’ ability to dilate and to increase the expression of vasoconstrictive factors, such as endothelin-1, thereby contributing to vascular stiffness. Meanwhile, SASP factors released by senescent endothelial cells have been shown to recruit inflammatory cells, increase endothelial permeability, and disrupt barrier function, thereby promoting local inflammation and vascular dysfunction. Animal studies have demonstrated a significant decrease in NO bioavailability in the aortic endothelium of aged mice, leading to increased vascular stiffness[43]. In a cohort of healthy adults aged 20-91 years, flow-mediated dilation of the brachial artery exhibited a marked age-related decline, approximately 64% in women and 47% in men, indicating substantial impairment of endothelial function during aging[44]. Therefore, while endothelial aging may not directly cause hypertension or atherosclerosis, it likely establishes a permissive environment for their development by reducing vascular compliance and promoting inflammatory and procoagulant states.

Phenotypic transformation of smooth muscle cells and atherosclerosis

Vascular smooth muscle cells (VSMCs) play a pivotal role in vascular remodeling and the progression of atherosclerosis. With the aging process, VSMCs gradually shift from a contractile phenotype to a synthetic phenotype. These phenotypic changes (reduced contractile protein expression and increased extracellular matrix secretion/calcification) impair VSMC contractility and increase matrix deposition, which collectively weaken fibrous cap stability and enhance plaque vulnerability[45]. Mechanistically, p53/p21-mediated cell cycle arrest, activation of mechanistic target of rapamycin (mTOR) signaling, and telomere shortening are all considered drivers of VSMC senescence[46]. Particularly within atherosclerotic plaques, aging VSMCs are more susceptible to apoptosis and calcification, which compromises the stability of the fibrous cap and thereby increases the risk of plaque rupture[47]. Single-cell sequencing studies have revealed the presence of specific “aging-like” VSMC subpopulations in arterial plaques of elderly patients, with gene expression profiles closely linked to inflammation and matrix remodeling[48]. This suggests that VSMC aging not only accelerates vascular hardening but may also influence plaque stability by altering the cellular composition. Therefore, VSMC aging is recognized as a significant driving force for the aging phenotype of atherosclerosis.

Myocardial cell senescence and heart failure

Cardiomyocytes, as highly differentiated terminal cells, largely lose their proliferative capacity. Their senescence manifests primarily through weakened contractile function, aberrant calcium ion processing, and disrupted energy metabolism. As age advances, mitochondrial function in cardiomyocytes declines, leading to an increase in ROS generation. This, in turn, causes the accumulation of protein and DNA damage, thereby activating cellular senescence pathways[49]. Recent studies indicate that telomere shortening is prevalent in the myocardial tissue of heart failure patients compared to normal controls, suggesting a strong link between myocardial aging and cardiac dysfunction. In contrast, heart failure with reduced ejection fraction (HFrEF) is more often associated with myocardial loss or injury[50]. Therefore, an aging myocardium alone does not directly cause heart failure. Instead, it diminishes compliance, elevates stiffness, and reduces energy utilization efficiency, making the heart more susceptible to HFpEF when coupled with conditions like hypertension, obesity, or metabolic disorders. This phenomenon also accounts for the high incidence of HFpEF observed in the elderly population. Moreover, HFpEF exhibits considerable heterogeneity, encompassing obesity-related, inflammatory, and sex-specific subtypes, each driven by distinct mechanisms and displaying unique clinical trajectories. The aging of skeletal muscle and exercise intolerance further exacerbate the syndrome, underscoring the systemic nature of HFpEF in older adults. Obesity-related HFpEF is driven by chronic volume overload, systemic inflammation, and metabolic dysregulation. Inflammatory HFpEF is characterized by the activation of immune cells and elevated levels of pro-inflammatory cytokines, both of which contribute to myocardial stiffness and diastolic dysfunction. Women are twice as likely as men to develop HFpEF, with obesity presenting a greater risk factor in women. Skeletal muscle aging and exercise intolerance are additional peripheral contributors contributing to the condition. Specifically, age-associated abnormalities in skeletal muscle energy metabolism are strongly linked to exercise intolerance in older HFpEF patients.

Cardiac fibrosis and impaired diastolic function

Cardiac fibrosis stands as a significant histological hallmark of the aging heart. With advancing age, the activation of cardiac fibroblasts increases, leading to excessive deposition of collagen types I and III. This process results in increased ventricular wall stiffness and subsequent diastolic dysfunction[51,52]. Mechanistically, TGF-β/Smad signaling pathway, the Wnt pathway, and oxidative stress all play roles in the development of age-related fibrosis. Animal models have demonstrated that inhibiting TGF-β activity can partially reverse myocardial fibrosis and improve diastolic function[53]. Moreover, age-related matrix remodeling is not solely characterized by collagen deposition but also involves an increase in the degree of collagen cross-linking, which further compromises ventricular compliance. Clinically, cardiac magnetic resonance imaging and serum biomarkers indicate a significant increase in myocardial interstitial fibrosis in the elderly, strongly correlating with diastolic dysfunction and an elevated risk of HFpEF[54,55]. Therefore, cardiac fibrosis can be viewed as a “structural phenotype” of the aging heart, and its presence renders the aging heart more vulnerable to adverse reactions to stress or volume loads.

Immunosenescence and inflammaging

The immune system undergoes significant remodeling with age, a process termed “immunosenescence”. This phenomenon is characterized by several key features, including decreased activity of hematopoietic stem cells, reduced T cell diversity stemming from thymus atrophy, and abnormal innate immune functions such as natural killer cells and macrophages. Concurrently, the body experiences a persistent state of chronic low-grade inflammation (inflammaging), evidenced by elevated serum levels of IL-6, tumor necrosis factor (TNF)-α, and C-reactive protein (CRP)[56]. Immunosenescence contributes to cardiovascular injury through multiple mechanisms. On one hand, the diminished efficiency of adaptive immunity impairs the body’s capacity to respond to cardiovascular injury. On the other hand, the sustained inflammatory microenvironment accelerates the loss of vascular endothelial function, promotes arteriosclerosis, and exacerbates myocardial fibrosis[57]. Population studies have demonstrated an independent association between high IL-6 levels and an increased risk of heart failure and coronary heart disease[58]. Conversely, lower inflammatory markers are commonly observed in centenarian populations[59], suggesting that inflammaging provides a crucial backdrop for the onset and progression of cardiovascular diseases. Therefore, immunosenescence and chronic low-grade inflammation collectively represent a “systemic soil” that influences the cardiovascular phenotype of aging, impacting the fate of various cells, including endothelial cells, VSMC, and myocardial cells.

AGING AND CLINICAL CARDIOVASCULAR PHENOTYPES

Molecular and cellular aging mechanisms culminate in distinct clinical cardiovascular phenotypes. Rather than creating new diseases, aging reshapes the susceptibility, presentation, and progression of common cardiovascular diseases by altering tissue structure, functional reserve, and stress responsiveness. Aging thus acts as a permissive and amplifying determinant, lowering disease thresholds and modifying clinical expression across multiple cardiovascular conditions.

Atherosclerosis and plaque instability

Atherosclerosis, a prominent vascular manifestation of aging, is intricately linked to the aging process itself. As individuals age, a confluence of endothelial dysfunction, phenotypic switching of VSMCs, and chronic low-grade inflammation establishes a vascular environment marked by diminished repair capabilities and persistent inflammatory activation. This milieu, in turn, promotes the accumulation of lipids, the formation of plaques, and the progressive growth of lesions.

Atherosclerotic plaques in older adults exhibit distinct compositional features compared to those in younger individuals, including increased calcification, thinner fibrous caps, larger necrotic cores, and a heightened inflammatory burden. These structural characteristics contribute to increased plaque vulnerability, even at comparable lipid levels[60]. Clinical data corroborate this, showing that older patients experience higher rates of acute coronary syndromes despite similar or only modestly elevated low-density lipoprotein cholesterol concentrations.

Aging significantly impacts not only the overall burden of atherosclerosis but also the biological behavior of existing plaques. Vascular wall cell senescence and age-associated alterations in intercellular communication hinder adaptive remodeling and destabilize lesion architecture. Consequently, aging acts as a crucial modifier of plaque stability and clinical risk, extending beyond traditional lipid-centric paradigms.

Heart failure: Aging as a determinant of phenotype

Heart failure stands as a quintessential clinical manifestation of cardiovascular aging, yet its relationship with the aging process varies substantially across phenotypic subtypes. HFpEF disproportionately affects older individuals and is increasingly recognized as a syndrome intrinsic to the aging heart.

Research indicates that the combined effects of myocardial cell aging, fibrotic deposition, and vascular stiffness impede the heart’s ability to fully relax under stress, leading to congestive symptoms during exercise or other stressors[61]. In contrast, HFrEF more frequently stems from myocardial infarction or dilated cardiomyopathy. While aging certainly increases the risk for HFrEF, it is not considered its primary driving force. Clinical cohort studies have consistently shown that the average age of patients with HFpEF is significantly higher than that of patients with HFrEF. Furthermore, HFpEF is often associated with age-related comorbidities such as hypertension, obesity, and diabetes[62]. This evidence suggests that HFpEF can be characterized as a “clinical syndrome of the aging heart”, whereas HFrEF more accurately reflects structural damage following myocardial injury.

Hypertension and vascular aging

Blood pressure levels typically rise with age, particularly systolic blood pressure, a phenomenon closely linked to increasing vascular stiffness. As the aging process advances, the aorta and large arteries progressively lose their elasticity due to increased collagen deposition and cross-linking, alongside intensified degradation of elastin. This leads to a significant decline in vascular compliance. Consequently, systolic blood pressure rises, diastolic blood pressure relatively decreases, and pulse pressure difference increases, forming the typical phenotype of isolated systolic hypertension observed in elderly individuals. Extensive clinical research has demonstrated that pulse wave velocity (PWV), a key indicator of vascular stiffness, correlates strongly with age and independently predicts the risk of cardiovascular events[63,64]. Notably, vascular stiffness not only heightens the prevalence of hypertension but also promotes ventricular hypertrophy and diastolic dysfunction by increasing the left ventricle’s afterload[65]. Thus, vascular stiffness serves as a critical link between aging and hypertension, making the phenotype and detrimental effects of hypertension more pronounced in the elderly population.

Arrhythmia and electrophysiological vulnerability

The incidence of cardiac arrhythmias rises significantly with age, with atrial fibrillation (AF) being the most prevalent age-related form. In aging hearts, several factors contribute to an increased susceptibility to arrhythmia: A reduction in sinoatrial node cells, altered ion-channel expression and membrane excitability, and heterogeneous atrial conduction due to fibrosis. Additionally, abnormal calcium processing within myocardial cells and prolonged action potential duration are common in aging, making myocardial tissue more prone to triggered activity[66]. The prevalence and incidence of AF increase sharply in older populations, with age being one of the strongest independent risk factors. Older adults also face an elevated risk of ventricular arrhythmias, partly due to conduction blocks and reentrant formations caused by fibrosis[67]. Beyond atrial and ventricular arrhythmias, aging predisposes individuals to sinoatrial node dysfunction, sick sinus syndrome, and conduction abnormalities like bundle branch blocks, primarily driven by progressive myocardial fibrosis and altered ion channel expression. It is crucial to recognize that arrhythmias are not solely a consequence of aging itself but rather result from the combined effects of age-related electrophysiological changes and comorbidities such as hypertension, heart failure, and coronary heart disease.

EVALUATION TOOLS AND BIOMARKERS

Current approaches to assessing cardiovascular aging

As research into cardiovascular aging advances, accurately assessing an individual’s aging state and associated risks has become a critical translational challenge. Traditional chronological age indicators are insufficient to capture individual biological differences. Consequently, recent years have seen the emergence of multidimensional assessment tools, including imaging modalities, circulating biomarkers, and molecular markers, particularly epigenetic clocks.

Imaging-based assessment of cardiovascular aging

Imaging techniques offer crucial tools for the non-invasive assessment of cardiovascular structure and function. Vascular ultrasound is frequently employed to measure carotid intima-media thickness and plaque burden, which reflect the extent of atherosclerosis and the process of vascular aging[68]. The measurement of PWV, especially carotid-femoral PWV, is widely considered the reference standard for non-invasive assessment of arterial stiffness and is independently associated with cardiovascular events[69]. However, PWV has methodological limitations, including variability in distance measurement, operator dependency, and a lack of well-defined reference values. Complementary imaging modalities, such as computed tomography-based vascular assessment and coronary artery calcium (CAC) scoring, offer additional information on vascular aging and cardiovascular risk[47]. CAC scoring, in particular, has been highlighted as a simple measure widely associated with biological aging[70]. At the cardiac level, echocardiography and cardiac magnetic resonance can evaluate diastolic function, myocardial fibrosis, and tissue characteristics. T1 mapping and late gadolinium enhancement imaging are extensively employed to identify myocardial fibrosis and characterize myocardial tissue remodeling. These imaging indicators not only reveal structural remodeling associated with aging but also serve as tools for early disease screening and evaluating therapeutic efficacy.

Myocardial deformation imaging offers a valuable complement to traditional vascular measures for assessing cardiovascular aging[71]. Specifically, speckle-tracking echocardiography can detect subtle myocardial dysfunction that conventional echocardiography might miss. Left ventricular global longitudinal strain, for instance, decreases with age even when ejection fraction is preserved, and it predicts adverse outcomes, with notable sex-specific differences[72]. Furthermore, left atrial strain which encompasses reservoir, conduit, and booster pump components is gaining recognition in the context of cardiovascular aging. It shows particular promise for the early identification of HFpEF in older adults. These deformation parameters provide incremental value beyond standard imaging indices.

Circulating biomarkers of aging-related cardiovascular risk

Circulating factors in the blood serve as easily accessible indicators reflecting the processes of aging. Inflammatory factors, such as IL-6, TNF-α, and high-sensitivity CRP, are associated with the risk of arteriosclerosis and heart failure, making them representative markers of “inflammaging”[73]. Proteomic screens in organs with high plasma protein turnover have further expanded the list of candidate biomarkers. For example, comparative isobaric tags for relative and absolute quantitation profiling in aged kidneys identified 13 plasma-accessible proteins (including FN1, APOE, IGFBP7, TIMP1, and SERPINE1) that correlate with renal aging and overlap with cardiovascular SASP profiles, suggesting their potential as systemic aging biomarkers across different organs[74]. Alongside these novel protein candidates, established cardiac-specific biomarkers like N-terminal pro-brain natriuretic peptide and high-sensitivity troponin can predict heart failure and cardiovascular events in asymptomatic individuals. Indicators at the circulating cell level are also gradually attracting attention, such as telomere length in peripheral blood mononuclear cells and the expression patterns of age-related genes (p16INK4a, p21CIP1), which have been suggested as molecular windows into cardiovascular biological age[75]. These blood markers offer a convenient approach for large-scale epidemiological studies and clinical risk assessment.

Beyond these established markers, emerging biomarkers linked to cellular senescence and inflammaging show promise in assessing cardiovascular aging. Growth differentiation factor-15, a cytokine associated with the SASP, increases with age and predicts all-cause mortality[76]. Soluble ST2, a marker of myocardial stretch and fibrosis, predicts incident heart failure and cardiovascular death in older adults[77]. Galectin-3, implicated in fibrosis and inflammation, is associated with myocardial dysfunction in aging cohorts[78]. Circulating microRNAs, including miR-23a-3p and miR-92a-3p, are independently associated with cardiovascular outcomes in older adults[79]. Additionally, extracellular vesicle (EV) profiling, particularly through the EV aging index, aids in assessing biological aging and stratifying cardiovascular risk[80]. Collectively, these biomarkers complement traditional markers by offering molecular insights into the senescent and inflammatory processes that drive cardiovascular aging.

Epigenetic clocks and biological age

In recent years, epigenetic clocks, which are cutting-edge tools for measuring aging molecules, have been increasingly applied in cardiovascular research[81]. The models by Hannum et al[82] and Horvath[83], for instance, predict an individual’s biological age based on DNA methylation patterns with high accuracy. Studies have demonstrated that epigenetic age acceleration correlates with an elevated risk of atherosclerosis, coronary heart disease, and heart failure[29,84]. Furthermore, geriatric cohort studies have revealed a close association between epigenetic clocks and PWV, decreased cardiac diastolic function, and cardiovascular mortality[85]. In the future, a comprehensive “multi-omics aging score” that integrates blood phenotypes and imaging parameters is anticipated to become a standardized assessment tool for cardiovascular aging. Beyond DNA methylation-based clocks, emerging proteomic and metabolomic aging scores derived from high-throughput profiling of circulating proteins and metabolites offer complementary approaches for quantifying biological age and may promote cardiovascular risk prediction.

Social determinants of health (SDOH) influence cardiovascular risk factors and outcomes across the lifespan, thereby accelerating cardiovascular aging in socially vulnerable populations[86]. Structural determinants, such as ethnicity, geographic context, and education, begin to impact cardiovascular aging early in life. In contrast, intermediary determinants like food security, financial security, transportation access, environmental exposures, and social connection exert particularly strong effects during adulthood and elderhood. A recent analysis of over 280000 individuals demonstrated that financial strain and food insecurity were the most significant SDOH drivers of accelerated cardiac aging, with effects surpassing those of traditional risk factors[87]. These social exposures operate through biological pathways, including epigenetic age acceleration and accelerated arterial dysfunction. Integrating SDOH into cardiovascular aging assessment is crucial for identifying high-risk populations and designing equitable prevention strategies.

INTERVENTIONABLE DIRECTIONS AND TRANSLATIONAL RESEARCH

Interventionable directions and translational research in cardiovascular aging

With a deeper understanding of the molecular mechanisms underlying cardiovascular aging, several intervention strategies capable of reversing or alleviating the “aging phenotype” have progressed to preclinical or clinical validation stages. Broadly, these interventions can be categorized as: Lifestyle and metabolic interventions, anti-inflammatory and immune regulation, senotherapeutics targeting senescent cells, mTOR/nicotinamide adenine dinucleotide (NAD⁺)/ mitochondrial regulation, and more advanced epigenetic/reprogramming strategies. The subsequent text summarizes the evidence, potential applications in cardiovascular diseases, and translational considerations for each category. Figure 3 illustrates a summary of current and emerging therapeutic strategies targeting cardiovascular aging.

Figure 3 Therapeutic strategies targeting cardiovascular aging. Interventions are categorized according to their current evidence level: Established therapies with cardiovascular outcome data (green), early-phase clinical studies with limited human evidence (yellow), and preclinical/experimental strategies requiring further validation (red). CVD: Cardiovascular disease; MI: Myocardial infarction; CRP: C-reactive protein; NMN: Nicotinamide mononucleotide.

Lifestyle interventions and modulation of biological aging

Controlling diet represents a highly practical approach to mitigating the effects of aging. Prior research indicates that overnutrition can impede adaptive cellular stress responses by activating intracellular nutritional sensors, thereby hindering sensor detection and suppressing catabolic processes[3]. Conversely, calorie restriction has been demonstrated to extend lifespan and confer protection against diabetes, tumors, and cardiovascular diseases in various experimental models[88]. More recent findings suggest that lithocholic acid (LCA) interacts with TULP3, subsequently modulating sirtuin-v-ATPase and adenosine 5’-monophosphate-activated protein kinase signaling pathways[4,89]. This mechanism appears to replicate some of the beneficial effects observed with calorie restriction in experimental systems. Nevertheless, the clinical applicability and the precise extent to which LCA contributes to the benefits of calorie restriction in humans still require further investigation. Furthermore, exercise has also been proposed as a promoter of healthy aging[90]. Studies reveal that engaging in mixed exercise modalities can yield numerous advantages, including improved cardiovascular and pulmonary health, reduced blood pressure, and enhanced insulin sensitivity. Growing evidence also links regular aerobic exercise to a slower rate of epigenetic aging, as indicated by a diminished epigenetic age acceleration in physically active individuals.

Anti-inflammatory strategies and immune remodeling

Chronic low-grade inflammation is a defining characteristic of aging and a significant factor in the development of cardiovascular pathology. Consequently, the pharmacological modulation of inflammatory pathways has emerged as a promising strategy for slowing cardiovascular aging. In preclinical models, metformin has been shown to inhibit cellular senescence, reduce SASP signaling, and limit fibrotic remodeling[91]. Clinical evidence supporting interventions targeting inflammation is exemplified by the CANTOS trial, where inhibition of IL-1β with canakinumab decreased recurrent cardiovascular events independently of lipid lowering[92]. However, this trial did not show a reduction in overall mortality and was associated with an elevated risk of fatal infections. Similarly, low-dose colchicine demonstrated cardiovascular benefits in post-myocardial infarction populations, reinforcing the idea that attenuating inflammatory signaling can modify cardiovascular risk[93]. Future strategies might focus on more selective targeting of upstream inflammatory sensors, such as the NOD-like receptor thermal protein domain associated protein 3 inflammasome, as well as approaches aimed at restoring immune balance rather than broadly suppressing immune function. Such precise immune modulation is especially pertinent in older individuals, where excessive immunosuppression could entail substantial risks.

Senotherapeutics: Senolytics and senomorphics

Senolytics are a class of drugs designed to selectively induce apoptosis in senescent cells. Their mechanism of action exploits the dependence of senescent cells on specific pro-survival pathways. For instance, the combination of dasatinib (D) and quercetin (Q) eliminates senescent cells by inhibiting pathways such as BCL-2 and phosphatidylinositol 3-kinase. In animal models of atherosclerosis, senolytic treatment (such as D + Q or BCL-2/B-cell lymphoma-extra large inhibitors like navitoclax/ABT-263) has been shown to reduce the burden of senescent cells within plaques. Some studies also indicate improvements in fibrous cap stability and inflammatory profiles. However, the impact on overall lesion size remains inconsistent across different models[94,95]. Early pilot human trials, including open-label and small randomized studies in idiopathic pulmonary fibrosis, have demonstrated that intermittent D + Q administration can decrease senescence-associated biomarkers and modestly improve functional outcomes. These results suggest feasibility and biological activity, though cardiovascular benefits have not yet been confirmed[96]. Importantly, senolytic agents that target anti-apoptotic pathways also present notable safety concerns. In aged nonhuman primates, intermittent navitoclax administration induced reversible thrombocytopenia, although overall tolerability was acceptable[97]. In oncology trials, BCL-2/B-cell lymphoma-extra large inhibitors like navitoclax have been repeatedly associated with dose-dependent thrombocytopenia and neutropenia, which may limit their chronic use in cardiovascular populations[98]. Beyond these safety concerns, off-target effects and potential impairment of tumor surveillance represent additional barriers to chronic senolytic use in otherwise healthy older populations. Long-term safety data in humans remain limited, and optimal dosing regimens have not been established. Therefore, future translational studies should prioritize randomized evaluations using intermediate and imaging endpoints (e.g., endothelial function, plaque composition, or myocardial fibrosis), coupled with careful hematologic and infection monitoring, before progressing to large-scale outcome trials.

In contrast, senomorphics aim to mitigate the deleterious effects of senescent cells without eliminating them, primarily by suppressing the SASP production. Agents targeting nuclear factor kappa-B, Janus kinase/signal transducer and activator of transcription, mTOR signaling, or epigenetic regulators may preserve the beneficial functions of senescence while limiting chronic inflammation[99]. Despite their theoretical advantages, senomorphics encounter hurdles concerning tissue specificity, the longevity of their effects, and the potential for disrupting immune surveillance.

mTOR inhibition and metabolic-immune regulation

The mTOR integrates nutrient availability, growth signals, and stress responses, playing a central role in aging regulation. In preclinical models, mTOR inhibition attenuates SASP, reduces fibrotic remodeling, and improves organ function[100,101]. Clinical studies of low-dose mTORC1 inhibitors, such as everolimus, have demonstrated improved vaccine responsiveness and reduced infection rates in older adults, indicating an ability to enhance immune function rather than uniformly suppress it[102]. In the cardiovascular context, inhibiting mTOR shows promise for modulating metabolic inflammation, reducing fibrosis, and enhancing vascular function. However, concerns about metabolic side effects and long-term immunological consequences mean that future trials must carefully select patients and determine dosing strategies.

NAD⁺ supplementation and mitochondrial restoration

NAD⁺ metabolism critically regulates mitochondrial function, redox balance, and inflammatory signaling. Age-associated declines in NAD⁺ levels contribute to mitochondrial dysfunction and amplify pro-inflammatory SASP signaling[103]. Supplementation with NAD⁺ precursors, such as nicotinamide mononucleotide and nicotinamide riboside, has been shown to restore mitochondrial function and improve cardiovascular phenotypes in animal models. Early human studies indicate that NAD⁺ precursor supplementation is generally safe and effectively increases circulating NAD⁺ levels[104]. Cardiovascular outcome data remain limited, so these interventions should be considered investigational. Further research is needed to establish their cardiovascular efficacy in humans, particularly when combined with lifestyle or exercise-based interventions.

Epigenetic reprogramming and emerging rejuvenation strategies

A recent study analyzed gene expression data from over 40 human tissues and 20 diseases, revealing that partial reprogramming, induced by Yamanaka factors, can significantly reduce the general upregulation of mesenchymal genes across multiple cell types. This process also alters the composition of stromal cell populations prior to dedifferentiation and acquisition of pluripotency, effectively revitalizing aging transcriptomes at both cellular and tissue levels[105]. Partial reprogramming has been demonstrated in mice to reverse several aging phenotypes, offering a proof of concept for future “rejuvenation” strategies[106]. However, epigenetic reprogramming carries potential risks of tumor formation and issues with controllability, remaining in the early stages of exploration. In the short term, a more realistic approach involves applying its underlying mechanisms to screen for small molecule compounds or target compounds. Table 2 lists representative original experiments and clinical studies[107-109].

Table 2 Representative preclinical and human studies of interventions relevant to cardiovascular aging.

Ref.	Model/population	Study design or phase	Primary endpoint(s)	Adverse events	Main findings	Translational evidence and interpretation
Roos et al[107]	Aged/atherosclerotic mice (n = NA)	Preclinical (animal)	Vasomotor function, vascular stiffness, plaque size/composition	Not reported	Vascular senescent cells (↓); endothelial function (↑)	Preclinical
Karnewar et al[95]	ApoE-/- mice (advanced plaque) (n = NA)	Preclinical (animal)	Plaque stability (fibrous cap thickness), mortality	Not reported	Plaque stability (↓); mortality (↑ > 50%; stage-dependent effect)	Preclinical
Garrido et al[94]	Preclinical atherosclerosis models (n = NA)	Preclinical (mechanistic and intervention)	Senescence marker specificity, plaque burden, inflammation	Non-specific effects	Variable plaque effects (↑, context and lineage-specific)	Preclinical
Mannick et al[102]	Older adults (≥ 65 years) (n = 264)	Phase II	Influenza vaccine response (antibody titer)	Mostly grade 1-2: Mouth ulceration, headache, nausea, stomatitis, fatigue	Vaccine response (↑)	Early human evidence
Martens et al[108]	Healthy middle-aged/older adults (n = 24)	Pilot RCT	Blood NAD+ levels, aortic stiffness (PWV)	Well-tolerated; no serious AEs reported	Blood NAD+ (↑); aortic stiffness (pilot) (↓)	Early human evidence
Ridker et al[109]	Post-MI, hsCRP ≥ 2 mg/L (n = 10061)	Phase III	MACE (nonfatal MI, stroke, CV death)	Fatal infections (↑) (1.16% vs 0.69%); leukopenia	MACE (↓) (LDL-C independent)	Cardiovascular outcome evidence; not established for cardiovascular aging
Tardif et al[93]	Recent MI patients (n = 4745)	Phase III	Ischemic CV events (CV death, resuscitated arrest, MI, stroke, urgent revascularization)	Gastrointestinal symptoms: Colchicine 23% vs placebo 20.8%	Ischemic CV events (↓)	Cardiovascular outcome evidence; not an aging-specific indication
Ridker et al[110]	Patients with post-MI or multivessel coronary disease and type 2 diabetes or metabolic syndrome (n = 4786)	Randomized, double-blind, placebo-controlled phase III trial	Major adverse CV events and inflammatory biomarkers	Liver enzyme levels, leukopenia, and selected non-basal-cell skin cancers (↑)	Low-dose methotrexate did not reduce CV events or circulating IL-1β, IL-6, or CRP	Neutral CV outcome; pathway-specific effects of anti-inflammatory therapy
Justice et al[96]	Patients with idiopathic pulmonary fibrosis (n = 14)	Open-label pilot study	Retention and completion rates	1 SAE (pneumonia, resolved)	Intermittent dasatinib plus quercetin showed feasibility and exploratory functional improvement	First-in-human senolytic evidence; no CV efficacy endpoint

The table summarizes representative preclinical and human studies of interventions relevant to cardiovascular aging. The evidence spans experimental animal studies, early human investigations, and large-scale randomized cardiovascular outcome trials. The inclusion of cardiovascular outcome trials indicates clinical evidence for the corresponding biological pathway but does not imply that these interventions are established or approved specifically for cardiovascular aging. NA: Not applicable; MI: Myocardial infarction; hsCRP: High-sensitivity C-reactive protein; NAD⁺: Nicotinamide adenine dinucleotide; RCT: Randomized controlled trial; PWV: Pulse wave velocity; MACE: Major adverse cardiovascular events; CV: Cardiovascular; AE: Adverse event; LDL-C: Low-density lipoprotein cholesterol; IL: Interleukin; CRP: C-reactive protein.

RESEARCH GAPS AND PROSPECTS

Before discussing these gaps, it is important to acknowledge the inherent limitations of much of the evidence reviewed in this manuscript. Many foundational studies originate from preclinical models that may not fully recapitulate human cardiovascular aging, and positive findings in animal models have not consistently translated into clinical benefit. Even among human studies, findings are often inconsistent, with discrepancies attributed to heterogeneity in study design, measurement techniques, and population characteristics. These caveats necessitate a cautious interpretation of the evidence and underscore the need for rigorous, well-powered clinical trials with aging-relevant endpoints. Despite rapid advancements in elucidating the mechanisms and translational potential of cardiovascular aging, substantial gaps persist between experimental insights and clinical application. These challenges encompass an incomplete mechanistic understanding, limitations in aging assessment tools, and barriers to effective clinical translation. Resolving these issues is essential for advancing cardiovascular aging from a conceptual framework to a clinically actionable paradigm.

Incomplete understanding of integrated aging mechanisms

The available studies have identified critical roles for cellular senescence, mitochondrial dysfunction, telomere attrition, epigenetic alterations, and impaired proteostasis in cardiovascular aging. However, the interactions among these hallmarks remain incompletely defined. Most available evidence derives from reductionist models that isolate individual mechanisms, whereas aging in the human cardiovascular system likely reflects complex, context-dependent cross-talk among multiple pathways.

For example, the SASPs may exert both deleterious and adaptive effects, depending on factors such as timing, tissue context, and the efficiency of immune clearance. Similarly, the causal relationships linking immunosenescence, inflammaging, and cardiovascular remodeling remain controversial, with much of the current evidence being associative rather than interventional. Even for widely studied biomarkers like telomere length, the evidence of a causal link to cardiovascular disease is still debated. Significant heterogeneity across studies partially accounts for these discrepancies. Future research must transcend single-pathway models, moving toward integrative, systems-level approaches that capture the dynamic interplay among aging mechanisms across various cell types and disease stages.

Limitations in biomarkers and aging assessment tools

A comprehensive and standardized measure of biological aging in the cardiovascular system remains elusive, despite numerous proposed imaging parameters, circulating biomarkers, and molecular indicators. Current limitations in measurement techniques, diverse patient populations, and the confounding effects of comorbidities hinder both cross-study comparisons and clinical interpretation.

Moreover, many suggested biomarkers are not specific to aging processes, being influenced instead by an individual’s metabolic state, inflammatory responses, and environmental exposures. The majority of existing data comes from cross-sectional analyses, with a notable absence of large-scale longitudinal research to validate these markers as predictors of cardiovascular outcomes or responsiveness to therapies. Consequently, there is an urgent need to develop cardiovascular aging metrics that are standardized, reproducible, and validated over time.

The integration of multi-omics data with advanced imaging and artificial intelligence-based analytics offers a promising avenue for constructing composite aging scores capable of dynamically tracking cardiovascular aging trajectories and informing personalized risk stratification.

Barriers to clinical translation of aging-targeted interventions

A growing number of interventions targeting aging has shown promise in conferring cardiovascular benefits within preclinical models; however, their translation to human populations continues to face significant hurdles. Foremost among these are safety concerns, especially pertinent for strategies involving senolytics or the sustained modulation of nutrient-sensing pathways. Potential adverse effects, including thrombocytopenia, immunosuppression, and metabolic dysregulation, could substantially impede their widespread clinical adoption. Furthermore, even approaches that have demonstrated considerable promise in preclinical studies, in some instances, yielded controversial or even detrimental results. For example, senolytic therapies have been linked to exacerbated cardiac dysfunction, plaque instability, and elevated mortality rates in specific animal models. Similarly, high-dose nicotinamide riboside supplementation unexpectedly led to an increase in aortic plaque lesions and systemic inflammation in atherosclerotic mice. In the anti-inflammatory domain, while CANTOS demonstrated benefit with canakinumab, the cardiovascular inflammation reduction trial testing low-dose methotrexate yielded neutral results, and the CANTOS trial itself did not show a reduction in overall mortality and raised infection-related safety concerns that have limited clinical adoption[110]. To summarize the major intervention classes reviewed, only anti-inflammatory agents (canakinumab and colchicine) have undergone evaluation in large-scale cardiovascular outcome trials. Senotherapeutics and NAD⁺-targeting interventions, however, are largely still in preclinical or early-phase clinical stage, with no agents yet approved for cardiovascular aging indications.

Additional challenges include the uncertainty surrounding optimal patient selection, the ideal timing of intervention, and the appropriate duration of treatment. It remains unclear whether therapies targeting aging should commence before the overt onset of disease, be applied selectively to high-risk individuals, or be integrated with conventional cardiovascular treatments. Furthermore, most clinical trials to date have relied on surrogate metabolic or inflammatory endpoints, rather than measures directly reflecting cardiovascular aging.

Innovative trial designs, incorporating structural and functional endpoints such as arterial stiffness, myocardial fibrosis, or electrophysiological vulnerability, could accelerate the evaluation of aging-targeted interventions while reducing reliance on long-term, event-driven outcomes.

Future outlook

Advancing the field of cardiovascular aging will necessitate coordinated efforts across basic, translational, and clinical research domains. Key priorities include: (1) Conducting cross-scale mechanistic studies that integrate single-cell omics, spatial transcriptomics, and multimodal imaging to construct spatiotemporal maps of cardiovascular aging; (2) Developing standardized, composite biomarkers that accurately reflect biological aging rather than chronological time; and (3) Implementing precision intervention strategies that combine lifestyle modification, pharmacological targeting, and immune or metabolic modulation.

Equally important are ethical and policy considerations. Interventions targeting aging will predominantly involve older populations and must therefore balance long-term safety, accessibility, and health equity. Ensuring that advancements in geroscience translate into broadly available cardiovascular benefits, rather than selective longevity enhancement, will be crucial for responsible clinical implementation.

Building upon the SDOH discussed earlier in this review, future research must address critical gaps in diversity and representation. The majority of aging studies have been conducted in White populations and high-income countries, which limits the generalizability of findings. Furthermore, sex-specific differences in cardiovascular aging remain underexplored and warrant dedicated investigation. The emergence of precision geroscience, which tailors interventions based on individual biological age profiles, and implementation science, which translates geroprotective strategies into real-world clinical practice, will be essential for achieving equitable cardiovascular health in aging populations.

CONCLUSION

Cardiovascular aging serves as a paradigmatic example of how fundamental aging biology shapes organ-specific vulnerability to disease. Accumulating evidence indicates that interconnected hallmarks of aging, such as cellular senescence and the SASP, mitochondrial dysfunction, epigenetic remodeling, telomere attrition, and impaired proteostasis, form an integrated pathological network. This network drives conditions like atherosclerosis, HFpEF, hypertension, and arrhythmia by reducing vascular compliance, promoting VSMC phenotypic switching, amplifying myocardial fibrosis, and sustaining chronic inflammation. Furthermore, advances in biological age assessment, particularly epigenetic clocks and imaging-based measures of vascular and myocardial aging, offer quantitative tools to bridge geroscience with cardiovascular risk stratification. In parallel, progress in aging-targeted interventions, including lifestyle-based strategies, metabolic modulation, senotherapeutics, and the regulation of mTOR and NAD⁺ pathways, has shown the potential to modulate aging trajectories in preclinical models and selected early-phase clinical studies. Nevertheless, translating these approaches into cardiovascular practice presents substantial challenges. These include the limited standardization of aging biomarkers, insufficient longitudinal validation, and unresolved concerns regarding the long-term safety and optimal timing of interventions. Addressing these gaps will require well-designed randomized trials that prioritize structure- and function-based endpoints, which are reflective of biological aging, rather than relying solely on traditional disease-centric outcomes. Taken together, cardiovascular aging serves as a clinically accessible and quantifiable model system for testing geroscience hypotheses and evaluating aging-targeted interventions in humans. Integrating geroprotective strategies with established cardiovascular prevention and treatment paradigms promises to delay cardiovascular aging, reduce disease burden, and ultimately promote healthy longevity.